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Pathways Linking Birth Weight and Insulin Sensitivity in Early Adolescence: A Double Mediation Analysis.

ABSTRACT: Purpose:We examined pathways linking birth weight, weight gain from 0 to 2 years, and adiposity during childhood with insulin sensitivity in early adolescence. Methods:Data were from a longitudinal cohort of 630 Quebec white children with a parental history of obesity (Quebec Adipose and Lifestyle Investigation in Youth study). In a subsample of children born at term (n = 395), weight-for-length z score (zWFL) from 0 to 2 years were computed. At 8 to 10 years, the percentage of body fat was assessed using dual energy X-ray absorptiometry. At 10 to 12 years, the Matsuda insulin sensitivity index (ISI) and the homeostasis model assessment for insulin resistance were determined. A linear regression-based approach for mediation analysis was used to estimate the distinct pathways linking zWFL at 0 to 2 years to insulin sensitivity. Results:Every additional unit in zWFL at birth was associated with a 10% (95% CI, 5.26% to 14.85%) increase in the Matsuda ISI in early adolescence, independently of the weight at 0 to 2 years and in childhood. An indirect effect of zWFL at birth on the Matsuda ISI was also observed but in the opposite direction (-4.44; 95% CI, -7.91 to -1.05). This relation was mediated by childhood adiposity but not by weight gain from 0 to 2 years. The indirect effect of weight gain from 0 to 2 years, via childhood adiposity, also led to lower insulin sensitivity (-4.83%, 95% CI, -7.34 to -2.53). The findings were similar for the homeostasis model assessment for insulin resistance or when restricted to children with appropriate-for-gestational-age birth weights. Conclusions:A greater birth weight-for-length resulted in improved insulin sensitivity in early adolescence. However, in the presence of excess childhood adiposity, both a greater birth weight and a faster rate of weight gain from 0 to 2 years resulted in lower insulin sensitivity.

SUBMITTER: Van Hulst A

PROVIDER: S-EPMC6220441 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Pathways Linking Birth Weight and Insulin Sensitivity in Early Adolescence: A Double Mediation Analysis.

Van Hulst Andraea A Paradis Gilles G Benedetti Andrea A Barnett Tracie A TA Henderson Mélanie M

The Journal of clinical endocrinology and metabolism 20181201 12

<h4>Purpose</h4>We examined pathways linking birth weight, weight gain from 0 to 2 years, and adiposity during childhood with insulin sensitivity in early adolescence.<h4>Methods</h4>Data were from a longitudinal cohort of 630 Quebec white children with a parental history of obesity (Quebec Adipose and Lifestyle Investigation in Youth study). In a subsample of children born at term (n = 395), weight-for-length z score (zWFL) from 0 to 2 years were computed. At 8 to 10 years, the percentage of bo ...[more]

PMID: 30137396

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Project description:BackgroundVascular endothelial dysfunction is an essential part of the pathophysiology of type 2 diabetes and its complications. In type 2 diabetes, endothelial dysfunction is characterized by reduced insulin signaling and increased transendothelial transport of fatty acids (FA). As the Abl kinase inhibitor imatinib was previously shown to reverse type 2 diabetes and to inhibit VEGF signaling via Abl kinases, we studied the effect of imatinib on vascular insulin sensitivity and fatty acid transport in vivo and in vitro.MethodsC57/BL6J mice were fed a chow diet or Western diet (WD), and received daily imatinib injections for two weeks. Insulin-mediated vasoreactivity of resistance arteries was studied using intravital microscopy, and metabolic insulin sensitivity using the hyperinsulinemic-euglycemic clamp. The effect of imatinib on triglyceride content in skeletal muscle and heart in vivo was also determined. In vitro, the effect of imatinib on fatty acid transport was studied in human umbilical vein endothelial cells (HUVECs) by evaluating the effect of imatinib on fluorescently labeled FA uptake both under basal and VEGF-B-stimulated conditions.ResultsImatinib prevented the WD-induced weight gain in mice, independently from food intake. In line with this, imatinib enhanced insulin-mediated vasoreactivity of resistance arteries in the WD-fed mice. However, imatinib did not affect triglyceride content in muscle. In cultured endothelial cells, VEGF-B stimulation resulted in a time-dependent uptake of fatty acids in parallel with increased phosphorylation of the Abl kinase substrate Crk-like protein (CrkL) at Tyr207. Although imatinib effectively prevented VEGF-B-mediated Abl kinase activation, it had no effect on VEGF-B mediated endothelial FA uptake.ConclusionImatinib prevents weight gain and preserves insulin-mediated vasodilation in WD-fed mice, but does not affect endothelial FA transport despite inhibiting VEGF-B signaling. The beneficial effect of imatinib on insulin-mediated vasodilation may contribute to the anti-diabetic effects of imatinib.

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Pathways Linking Birth Weight and Insulin Sensitivity in Early Adolescence: A Double Mediation Analysis.

Publications

Pathways Linking Birth Weight and Insulin Sensitivity in Early Adolescence: A Double Mediation Analysis.

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